What is Leaky Gut Syndrome and how is it diagnosed?
Leaky Gut Syndrome (LGS) is an ailment characterized by a variety of symptoms including abdominal pain, fatigue, inflammation, gas, bloating, and intolerance to certain foods. It is thought to be caused by increased permeability of the intestinal lining, which is made up of structures called tight junctions. These structures are comprised of tightly knit cells that are essentially impermeable to fluids preventing the passage of undigested food particles, toxic waste products, bacteria, and viruses into the bloodstream. Researchers believe that this disruption of the seal of tight junctions allows the leakage of these substances into the bloodstream leading to inflammation throughout the body . To determine if a patient has a leaky gut, physicians will usually employ a mannitol-lactulose test in which a solution with these sugars is consumed and the urine produced is collected. The intestine easily absorbs mannitol while lactulose is only slightly absorbed. In a healthy individual urinalysis should indicate low levels of mannitol and high levels of lactulose however in a patient with a leaky gut both sugars will be present in high concentrations.
What processes go awry in LGS?
It has been hypothesized that LGS can be caused by problems with the body’s immune system. In the immune systems of patients with LGS there is a failure in the recognition of bodily structures as self, leading to attack of the host’s tissues by its own immune cells. While not all the factors have been assembled in the understanding of intestinal permeability there are some key factors that have been identified.
Immune cells present in the gut called mast cells have been shown to have an influence on intestinal permeability because they release the cytokine TNF-alpha. In patients suffering from LGS this signaling protein is improperly regulated which leads to inflammation of the gut . In addition there are alterations in what is known as the zonulin pathway in patients with autoimmune disorders. Zonulin signaling is an event in the gut that regulates the structure of tight junctions by modifying the expression of its components and hence altering the permeability of the intestinal barrier. In many autoimmune diseases zonulin is overexpressed leading to a compromised intestinal barrier .
How might cannabis alleviate the symptoms of Leaky Gut Syndrome?
Cannabis has a myriad of medicinal effects that have potential applications for alleviating the discomfort associated with LGS. Its ability to act as an antioxidant, influence intestinal permeability, as well as reduce nausea, inflammation, and pain response can be attributed to the relief it provides.
1. Cannabinoids have an influence on intestinal permeability
A study performed in 2011 published in the British Journal of Pharmacology showed that phytocannabinoids, specifically THC and CBD, cause a decrease in intestinal permeability in vitro using measurements of transepithelial electrical resistance (TEER) . In addition the application of these cannabinoids to intestinal epithelial cells caused an increase in the expression of the tight junction protein claudin-1, which is involved in cell-to-cell adhesion. This increase in expression could explain the overall observed decrease in intestinal permeability.
2. Cannabinoids are capable of suppressing the immune system
As previously mentioned dysregulation of immune responses can be partially attributed to the cause of leaky gut. The cannabinoid receptor CB2 is found on the surface of many types of immune cells that cause inflammation. The use of CB2 agonists like THC can result in suppression of the immune system, which could help mitigate some of the autoimmune problems that are associated with LGS .
3. Cannabinoids reduce inflammation
Compounds that act as CB1 receptor antagonists such as cannabidiol (CBD) are able of decreasing the expression of a cell signaling protein called tumor necrosis factor alpha (TNF-α) . The production of TNF-α leads to pro-inflammatory responses in the body therefore a reducing its production could greatly reduce intestinal inflammation .
Acidic cannabinoids are also capable of reducing inflammation by inhibiting cyclooxygenase (COX) enzymes. These enzymes are responsible for the production of compounds that mediate inflammatory responses such as prostaglandins and thrombaxanes  and are also the targets of over the counter non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetaminophen.
4. Cannabinoids act as antioxidants
Reactive oxygen species (ROS), compounds with unpaired electrons are prevalent in oxidative stress resulting in cell damage and inflammatory responses. The damaging effects of these compounds can be mitigated by cannabinoids which act as antioxidants in the body and stabilize these reactive molecules. Specifically, the cannabinoids THC and CBD have both been shown to exhibit antioxidant activity capable of neutralizing ROS .
5. Cannabinoids produce analgesia
Cells in the gut express the cannabinoid receptor CB2, which is partially responsible for producing the pain-relieving and anti-inflammatory effects of cannabis. In particular cannabis strains high in the terpene β-caryophyllene could provide the most benefit as this compound has been shown to be a functional CB2 agonist [10-11]. Some studies have also suggested that the probiotic L. acidophilus may also be a promising means to heighten these effects as the presence of these bacteria in the gut have been shown to cause an elevation in the expression of the CB2 receptor as well as have a protective role on the intestinal barrier [12-13].
The studies presented suggest that the ECS could be a potential therapeutic target in treating patients with LGS however further studies are needed to confirm these benefits. The evidence shown begs the question of the state of the ECS in patients with LGS. Are irregularities in endocannabinoid signaling part of the pathology of the disease as with other gastrointestinal and autoimmune ailments or are the findings that targeting the ECS could provide relief merely coincidence? Additionally could the use of the probiotic L. acidophilus enhance these therapeutic benefits? Until the federal government truly acknowledges the potential of this miraculous plant for the treatment of this crippling ailment these questions will remain unanswered.
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8. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.
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10. Klauke AL, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014;24(4):608-20.
11. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-104.
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What is COPD?
Chronic obstructive pulmonary disease (COPD) is an illness characterized by increased production of mucus and chronic inflammation of the airways resulting in reduced respiratory capacity. The two primary forms of COPD are chronic bronchitis, which produces a long-term cough with mucus, and emphysema, which leads to the progressive deterioration of the alveoli, the air sacs that allow for gaseous exchange in the lungs.
How is COPD treated?
COPD is typically treated with two different types of compounds: beta-adrenergic agonists and corticosteroids. Beta-adrenergic agonists are bronchodilators, which relax the smooth muscle surrounding the respiratory tract resulting in an increased diameter of the bronchial passages facilitating airflow. There are two types of beta-agonists: short-acting beta-adrenergic agonists (SABAs) such as albuterol and long-acting beta-adrenergic agonists (LABAs) such as salmeterol. SABAs are typically utilized in the event of an acute attack of shortness of breath while LABAs are used as a prophylactic measure. LABAs are commonly co-administered with corticosteroids such as fluticasone, which acts as a preventative against immune-mediated inflammation of the airways. One such formulation of LABAs and corticosteroids is the drug Advair, a combination of salmeterol and fluticasone.
How might cannabis help patients with COPD?
All smoke irritates the lung and aggravates COPD, but vaporized or ingested cannabis could potentially provide many benefits.
1. Bronchodilatory effects
Studies performed in the 1970’s at the University of California Los Angeles by Donald Tashkin have shown that both inhaled and orally ingested THC produce bronchodilation for up to two hours after administration . Further investigations by the Respiratory Pharmacology Laboratory in Paris have shown that CB1 receptor activation inhibits cholinergic contraction in a concentration-dependent fashion, offering a possible mechanism for acute bronchodilation associated with cannabis intake . Although smoked cannabis also has this effect, any kind of combustion creates other lung irritants that would be counterproductive for COPD treatment.
2. Suppression of the immune system
Those with COPD have a heightened immune response in the lungs and compounds in cannabis can lead to immunosuppression. Studies have shown that THC induces rapid mobilization of a specific subset of white blood cells that arise from bone marrow called myeloid-derived suppressor cells (MDSCs). These cells exert potent immunosuppressant properties by inhibiting the proliferation and activation of T-cells.
Additional studies performed at the University of South Carolina School of Medicine support these findings, where they determined that the intraperitoneal (injection into the body cavity) application of THC causes changes in microRNA expression that promotes the suppression of the immune system . Other findings using murine models have shown that intraperitoneal administration of THC results in a reduction of allergen-induced mucus production .
3. Anti-inflammatory effects
Cannabinoids have anti-inflammatory benefits through a variety of mechanisms. The acidic cannabinoids have a greater anti-inflammatory capacity than their non-acidic counterparts. Specifically studies by Ruhaak, et al., have shown that cannabinoids, in particular the acidic cannabinoids, are capable of inhibiting cyclooxygenases (COX-1 and COX-2); which are the enzymes responsible for the production of inflammatory compounds such as prostaglandins and thrombaxanes. Their investigation found that cannabigerolic acid (CBGA) was the most potent inhibitor of all the cannabinoids tested having an IC50 value of 4.6 x 10-4 M and 2.0 x 10-4 M for COX-1 and COX-2 respectively .
Recently studies performed at the University of Sao Paulo using cannabidiol have also shown some potential for improving the symptoms of COPD. They found decreased pulmonary inflammation and improvements in lung function in murine models of inflammatory lung disease using the inflammatory agent LPS, a component of the cell wall in gram-negative bacteria, as the inflammatory agent .
Other studies of terpene compounds, the aromatic components found in cannabis show anti-inflammatory benefits as well. In particular, beta caryophyllene has been shown to act as a dietary cannabinoid, attenuating inflammatory responses in various tissues in a CB2 receptor-dependent fashion [8-10]. In addition to being found in cannabis this terpene is also found in high concentrations in black pepper and cloves.
These studies indicate that cannabis could potentially act as a means to mitigate acute attacks of bronchoconstriction and may also act as a prophylactic measure for patients with COPD. However, human trials are needed to confirm some of these benefits and until restrictions by the federal government are lifted, a deeper understanding of these mechanisms will remain poorly understood.
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2. Grassin-delyle S, Naline E, Buenestado A, et al. Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors. Br J Pharmacol. 2014;171(11):2767-77.
3. Hegde VL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol. 2010;40(12):3358-71.
4. Hegde VL, Tomar S, Jackson A, et al. Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690. J Biol Chem. 2013;288(52):36810-26.
5. Reddy AT, Lakshmi SP, Reddy RC. Murine model of allergen induced asthma. J Vis Exp. 2012;(63):e3771.
6. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.
7. Ribeiro A, Almeida VI, Costola-de-souza C, et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol. 2014;:1-7.
8. Bento AF, Marcon R, Dutra RC, et al. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011;178(3):1153-66.
9. Horváth B, Mukhopadhyay P, Kechrid M, et al. β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med. 2012;52(8):1325-33.
10. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099-104.